Week 8 - Drugs and Receptors

Question 1

How do drugs produce their effects?

Answer 1

By interacting with targets

- These are mainly proteins

Question 2

What is molarity?

Answer 2

The concentration of drug molecules around receptors

• Critical in determining drug action
• Molarity (M) = (g/L)/Mr
• 1 mole contains 6x10^23 particles
• Drugs of equivalent molar concentration have the same concentration of drug molecules

Question 3

In terms of moles, how big is picomolar?

Answer 3

10^-12 M

Question 4

Describe the binding of drugs to receptors

Answer 4

• Usually reversible
• Governed by association and dissociation
• Binding obeys the law of mass action: i.e. it is related to the concentrations of both the reactants and products

Question 5

What are agonists?

Answer 5

Drugs that bind to receptors and cause a response

- They have both affinity and intrinsic affinity

Question 6

What are antagonists?

Answer 6

Drugs that bind to receptors but do not cause a response

• They have affinity but no efficacy
• They block the effects of agonists

Question 7

What dictates drug action?

Answer 7

Affinity and intrinsic efficacy

• Binding is governed by affinity
• Activation is governed by intrinsic efficacy

Question 8

What is intrinsic efficacy?

Answer 8

The ability to produce an active form of the receptor

Question 9

What is efficacy?

Answer 9

The ability of an agonist to cause a response in a cell or tissue

• Depends on intrinsic efficacy and cell/tissue-dependent factors
• Measured in relative terms
• – Agonists with different Emax values have different efficacy, but agonists with the same Emax values may not have identical efficacy

Question 10

What is Kd?

Answer 10

A measure of affinity

• Dissociation constant
• The lower the value, the higher the affinity
• At the Kd concentration, 50% of receptor will be occupied irrespective of the number of receptors

Question 11

What is EC50?

Answer 11

The effective concentration giving 50% of the maximal response
- A measure of potency

Question 12

What is potency?

Answer 12

The amount of drug needed to produce an effect

• A combination of both affinity and efficacy
• Also governed by the number of receptors (cell/tissue-dependent factor)

Question 13

What is IC50?

Answer 13

The inhibitory concentration giving 50% of the maximum inhibition
- For inhibitory drugs

Question 14

What could a drug response be?

Answer 14

• Change in signalling pathway

- Change in cell or tissue behaviour

Question 15

Which graphs can you use to measure the response of a drug?

Answer 15

• Concentration-response curves: when measuring a response in cells or tissues
• Dose-response curves: when measuring responses in a whole animal

Question 16

Which properties are required for a drug?

Answer 16

• Affinity (does it bind?)
• Efficacy (does it do what it is supposed to do?)
• Selectivity (off-target effects?)
• Drug metabolism/pharmacokinetics (how does the body deal with the drug)
• Physicochemical properties (solubility, pH, stbility, crystallinity)

Question 17

What are spare receptors?

Answer 17

Some tissues have more receptors than required to produce a maximum response

• I.e. They have spare receptors
• They increase sensitivity

Question 18

What is the effect of changing the number of receptors?

Answer 18

It changes agonist potency

- This can affect the maximal response

Question 19

When can the number of receptors be changed?

Answer 19

• In response to low activity: upregulation of receptors occurs to increase sensitivity
• In response to high activity: downregulation of receptors occurs in decrease sensitivity

Question 20

What are partial agonists?

Answer 20

Drugs that cannot produce a maximal effect, even with full receptor occupancy

• EC50 = Kd
• They can be more of less potent than full agonists
• Partial agonism is a property of the drug in a particular system (may be a partial agonist in tissue A, but a full agonist in tissue B)
• They have lower efficacy than full agonists in the same system

Question 21

What is reversible competitive antagonism?

Answer 21

A type of antagonism

• Depends on dynamic equilibrium between ligands and receptors
• The inhibition is surmountable (overcome) by addition of more agonist
• Commonest
• Causes a parallel shift to the right of the agonist concentration-response curve

Question 22

What is irreversible competitive antagonism?

Answer 22

A type of antagonism

• Occurs when the antagonist dissociates very slowly or not at all
• The inhibition is non-surmountable
• Causes a parallel shift to the right of the agonist concentration-response curve
• At higher concentrations, it suppresses the maximal response

Question 23

What is non-competitive antagonism?

Answer 23

A type of antagonism

• Generally a post-receptor or allosteric event
• Binds to the orthosteric site rather than the allosteric site, so molecules can still bind

Question 24

What is desensitisation?

Answer 24

A loss of functional response

Question 25

What are the mechanisms of desensitisation?

Answer 25

• Modification of the receptor by phosphorylation (short-term)
• Reversible receptor internalisation
• Down-regulation (long-term)

Question 26

What is drug tolerance?

Answer 26

A person’s diminished response to a drug

- Occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug

Question 27

What is supersensitivity?

Answer 27

The adaptive response by a tissue to overcome the effect of a drug treatment

• It may cause the cell to produce more of the receptors that are being blocked
• Has no effect when drug treatment is continued, but will cause a massive response when stopped

Question 28

What is homologous desensitisation?

Answer 28

Agonist-induced desensitisation of the same receptor that produced it
- I.e. When a receptor decreases its response to a signalling molecule when that agonist is in high concentration

Question 29

What is heterologous desensitisation?

Answer 29

Unresponsiveness of a cell to a variety of other agonists after prolonged stimulation by 1 agonist

• I.e. desensitises other receptors
• Usually occurs by receptor internalisation